title: Normalizing dopamine D2 receptor-mediated responses in D2 null mutant mice by virus-mediated receptor restoration: comparing D2L and D2S.
abstract: D2 receptor null mutant (Drd2(-/-)) mice have altered responses to the rewarding and locomotor effects of psychostimulant drugs, which is evidence of a necessary role for D2 receptors in these behaviors. Furthermore, work with mice that constitutively express only the D2 receptor short form (D2S), as a result of genetic deletion of the long form (D2L), provides the basis for a current model in which D2L is thought to be the postsynaptic D2 receptor on medium spiny neurons in the basal forebrain, and D2S the autoreceptor that regulates the activity of dopamine neurons and dopamine synthesis and release. Because constitutive genetic deletion of the D2 or D2L receptor may cause compensatory changes that influence functional outcomes, our approach is to identify aspects of the abnormal phenotype of a Drd2(-/-) mouse that can be normalized by virus-mediated D2 receptor expression. Drd2(-/-) mice are deficient in basal and methamphetamine-induced locomotor activation and lack D2 receptor agonist-induced activation of G protein-regulated inward rectifying potassium channels (GIRKs) in dopaminergic neurons. Here we show that virus-mediated expression of D2L in the nucleus accumbens significantly restored methamphetamine-induced locomotor activation, but not basal locomotor activity, compared to mice receiving the control virus. It also restored the effect of methamphetamine to decrease time spent in the center of the activity chamber in female but not male Drd2(-/-) mice. Furthermore, the effect of expression of D2S was indistinguishable from D2L. Similarly, virus-mediated expression of either D2S or D2L in substantia nigra neurons restored D2 agonist-induced activation of GIRKs. In this acute expression system, the alternatively spliced forms of the D2 receptor appear to be equally capable of acting as postsynaptic receptors and autoreceptors.
authors.affiliation: Research Service, Portland VA Medical Center, and Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: nevek@ohsu.edu.
authors.forename: K A
authors.initials: KA
authors.lastname: Neve
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: cpf21@case.edu.
authors.forename: C P
authors.initials: CP
authors.lastname: Ford
authors.affiliation: Research Service, Portland VA Medical Center, and Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: buckd@ohsu.edu.
authors.forename: D C
authors.initials: DC
authors.lastname: Buck
authors.affiliation: Department of Physiology & Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: grandyd@ohsu.edu.
authors.forename: D K
authors.initials: DK
authors.lastname: Grandy
authors.affiliation: Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA. Electronic address: rneve@MIT.EDU.
authors.forename: R L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: Research Service, Portland VA Medical Center, and Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: phillipt@ohsu.edu.
authors.forename: T J
authors.initials: TJ
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*
chemical_list: D018491:Dopamine Agonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D008694:Methamphetamine
keywords: D2 receptor null mutant mouse; dopamine D2 receptor; methamphetamine; potassium channel